Hepatitis B is a potentially life-threatening liver infection caused by the Hepatitis B virus (HBV). HBV infection can result in acute hepatitis (clinically apparent) or in a chronic disease. The clinical manifestations of acute infection include yellowing of the skin and eyes (jaundice); extreme fatigue; dark urine; nausea; diarrhea and vomiting; loss of appetite; and muscles, joints or abdominal pain. About 1-2% of individuals suffering from acute hepatitis B die from fulminant hepatic failure. Chronic HBV infection can stay undetected in the body for decades before it leads to an end-stage liver disease, including cirrhosis (scarring of the liver) and hepatocellular carcinoma.
HBV infection has a worldwide distribution. It is estimated that more than 2 billion of the global population has been infected with Hepatitis B virus (HBV). Of these, approximately 350 million have chronic liver infection and are at risk of serious illness and death from cirrhosis and hepatocellular carcinoma [World Health Organization; Fact sheet N° 204; August 2008].
Humans are the only reservoir of HBV. The virus is extremely contagious and is transmitted by percutaneous and mucosal exposure to blood or other body fluids of an infected person. Common modes of transmission may include mother-to-infant (perinatal), use of contaminated needles, contaminated blood transfusions and via unprotected sexual contact with an infected person. In addition, HBV is the major infectious occupational hazard of health workers, and most health care workers receive hepatitis B vaccine.
Advanced cases of viral caused hepatitis result in liver failure and orthotopic liver transplantation (OLT) is the only curative treatment. OLT refers to a procedure in which an impaired liver is removed from the patient's body and a healthy donor's liver is transplanted instead. However, although the diseased liver is removed, circulating virus may remain in the serum of the patient and in other body compartments; invade and infect the grafted liver; and consequently cause hepatitis recurrence. Thus, preventing HBV infection of the grafted liver is essential to avoid recurrence of hepatitis and crucial for maintaining liver function in OLT patients.
Passive immunization with Hepatitis B immunoglobulin (HBIG) has been shown to markedly reduce the incidence of Hepatitis B recurrence after liver transplantation and is now a well established approach used in OLT patients (Filipponi et al “Efficacy, safety, and pharmacokinetics of intramuscular hepatitis B immune globulin, Igantibe®, for the prophylaxis of viral B hepatitis after liver transplantation”. Dig Liver Dis. 2009). HBIG is derived from blood plasma of human donors expressing high titers of antibodies specific against hepatitis B surface antigen (anti-HBsAg). The antibodies bind to the surface antigen of the virus; inactivate circulating viruses; and prevent subsequent infection. Immunoglobulin can be administrated in one of the following routes: intravenously (IV), intramuscularly (IM) or subcutaneously (SC).
Moore and Quinn (“Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century”. Ann Allergy Asthma Immunol 2008; 101:114-121) provide a review on subcutaneous immunoglobulin therapy for patients with primary antibody deficiency (PAD). In their report it is indicated that immunoglobulin injected into the subcutaneous tissue has reduced intravenous bioavailability secondary to IgG catabolism and incomplete absorption from the subcutaneous space into the intravascular space. On the one hand according to US recommendations when transitioning from intravenous immunoglobulin (IVIG) to subcutaneous immunoglobulin (SCIG) therapy in patients with PAD the monthly IVIG dose is increased by 37% and divide by 4 to determine the weekly SCIG dose. The product is infused in multiple sites simultaneously with a total volume of up to 25 ml per infusion site. On the other hand dosing recommendations in European countries consists on a 1:1 dose conversion between IVIG and SCIG infusions. It was also reported by Ochs et al (“Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases”. J Clin Immunol. 2006; 26:265-273) that the average increase of the SCIG dose to 137% of that given intravenously dose is unnecessary and does not appear to confer any additional benefits in patients with primary immune deficiency diseases (PIDD).
In OLT patients, HBIG is typically administered by intravenous route concurrently with the grafting of the transplanted liver (the anhepatic phase), with subsequent daily dosing during each of the first 7 days post-transplantation. In the extended post-transplant period HBIG is administered monthly on an indefinite basis.
Most of the licensed immunoglobulin preparations are for intramuscular use (Stiehm et al. “Preparation and use of therapeutic antibodies primarily of human origin”. Biologicals. 2008; 36:363-374). The following are some of the commercially available HBIG formulations which are indicated for intravenous or intramuscular administration:
Omri-Hep-B™ (manufactured by Omrix Biopharmaceuticals) is prepared from human plasma collected from healthy anti-HBsAg high titer donors. Omri-Hep-B™ is used for passive immunization in the prevention of hepatitis B recurrence after liver transplantation. Omri-Hep-B™ is a sterile solution containing 5% protein of which at least 95% is human immunoglobulin G, 50 IU/ml of antibodies to HBsAg as the active ingredient, 10% maltose and water for injection. Omri-Hep-B™ is administered by intravenous infusion. HepaGam B™ (manufactured by Cangene Corporation) is indicated for the prevention of hepatitis B recurrence following liver transplantation, in HBsAg positive liver transplant patients. It is prepared from selected plasma donated by healthy, vaccinated and anti-HBsAg high titer donors. HepaGam B™ is formulated as a 5% (50 mg/mL) protein solution with 10% maltose and 0.03% polysorbate 80 at pH 5.6. It is available in 1 ml and 5 ml single dose vials containing about 312 IU/ml anti-HBsAg. HepaGam B™ is administered intravenously.
Hepatec® (manufactured by Biotest Pharma GmbH) is a human hepatitis B immunoglobulin solution for intravenous administration. 1 ml Hepatec® contains: 100 mg human plasma protein (10% protein) of which at least 95% is immunoglobulin G, 50 IU of antibodies to HBsAg, sodium chloride and water for injection.
HyperHEP B™ (manufactured by Talecris Biotherapeutics Inc.) is a solution which contains high quantities of anti-hepatitis B immune globulin for intramuscular administration. HyperHEP B™ is prepared from the plasma of healthy vaccinated anti-HBsAg high titer donors. It is formulated as a 15-18% protein solution at a pH of 6.4-7.2 in 0.21-0.32 M glycine. The formulation contains about 220 IU per ml anti-HBsAg.
BayHep B® (distributed by Bayer New Zealand Limited) is a hepatitis B immunoglobulin solution for intramuscular injection. 1 ml contains 217 IU anti-hepatitis B antibodies and 19.5 mg glycine. It is available in 0.5 ml neonatal single dose syringe, and 1 ml single dose vial.
Nabi-HB® (manufactured by Nabi® Biopharmaceuticals) is a sterile solution of immunoglobulin (5±1% protein) containing antibodies to hepatitis B surface antigen (anti-HBs). It is prepared from plasma donated by individuals with high titers of anti-HBs. Nabi-HB is formulated in 0.075 M sodium chloride, 0.15 M glycine, and 0.01% polysorbate 80, at pH 6.2. It contains 312 IU/ml anti-HBs and it is intended for administration in the intramuscular route.
According to the leaflet HyperHEP B™, BayHep B® and Nabi-HB® are indicated for acute exposure to blood containing HBsAg; perinatal exposure of infants born to HBsAg-positive mothers; sexual exposure to an HBsAg-positive person; and household exposure to persons with acute HBV infection.
Igantibe® (manufactured by Grifols) is a human anti-hepatitis B immunoglobulin for intramuscular use. Igantibe® is obtained from immunized plasma donors. The product contains 200 IU/ml with an IgG content of higher than 95% and HBIG content of 15.3%. It is formulated with glycine (2.25%), sodium chloride (0.30%) and sterile water for injection.
Various IV and/or IM dosing regimes of HBIG optionally combined with an anti-viral drug such as lamivudine are reported for OLT subjects.
Filipponi et al (2009) reported administration of Igantibe®, a specific HBIG (manufactured by Grifols), to adult patients who underwent liver transplantation more than 18 months earlier. IM administration of 2000 IU Igantibe® was carried out once every 14 days namely bimonthly for a period of 6 months. This regime allowed anti-HBs levels of ≧150 IU/L in the circulation of the subjects throughout the study period. In another study, Igantibe® was administered IM to OLT patients in a one monthly dose of 2000 IU and the HBV antibody titer were measured every month. This regime attained a protective antibody titer of >100 IU/L in the circulation for at least the first year after transplantation (Alonso et al. “Effectiveness of low-dose intramuscular anti-VHB immune globulin in the prophylaxis of viral B hepatitis reinfection after liver transplantation: preliminary report”.
Transplant Proc. 2003; 35:1850-1851). Both regimes (i.e. bimonthly and monthly administration) were considered protective and efficacious in prophylaxis of viral B hepatitis after liver transplantation.
Also, Faust et al. (“Cost-effective and safe ambulatory long-term immunoprophylaxis with intramuscular instead of intravenous hepatitis B immunoglobulin to prevent reinfection after orthotopic liver transplantation”. Clin Transplant. 2003; 17:254-258) reported that administration of 2000 IU IM HBIG given once a month together with 100 mg lamivudine per day is effective in prophylaxis of HBV re-infection in patients after OLT.
Yao et al. (“Intramuscular hepatitis B immune globulin combined with lamivudine for prophylaxis against hepatitis B recurrence after liver transplantation”. Liver Transpl Surg. 1999; 5:491-496) described a protocol comprising administration of IM HBIG and oral lamivudine (150 mg/d) in patients with HBV infection who underwent OLT. Patients with detectable HBV DNA at the time of OLT received 10,000 U (45 ml) of IV HBIG daily for 7 days, followed by 5 ml of IM HBIG weekly for the next 3 weeks, then every 3 weeks. Patients who were HBV DNA negative received on dose of IV HBIG (45 ml) during surgery, followed by 5 ml IM HBIG weekly for 4 weeks, then every 3 weeks. During a follow up of 15.6 months, all patients developed protective anti-HBs titers greater than 200 IU/L in the circulation and had no evidence of HBV recurrence.
Yoshida et al (“Liver transplantation for chronic hepatitis B infection with the use of combination lamivudine and low-dose hepatitis B immune globulin”. Liver Transpl Surg. 1999; 5:520-5.) studied the effectiveness of a post-transplantation prophylaxis protocol using a combination of lamivudine and HBIG in patients with chronic HBV infection. In the maintenance period HBIG therapy consisted of 2170 IU intramuscularly twice weekly, tapered to every 2 to 4 weeks by 12 months post-transplantation. Target serum HBIG titers were less than 500 IU/L for the first 6 months after OLT and then greater than 300 IU/L within the following 6 months. All patients achieved the target HBIG titer and allograft re-infection by HBV was prevented.
Using subcutaneous administration of immunoglobulin has several advantages. For example, subcutaneous IG infusions are well tolerated compared to IM administration, safe, and give the patient more independence compared to IV administration.
The reported dose for subcutaneous HBIG administration is similar or lower than that of intramuscular administration.
Subcutaneous administration of hepatitis B immunoglobulin (HBIG) in combination with lamivudine was previously reported (Powell et al. (“Subcutaneous administration of hepatitis B immune globulin in combination with lamivudine following orthotopic liver transplantation: effective prophylaxis against recurrence”. Clin Transplant. 2006; 20:524-525). According to the report the disclosed HBIG contained an antibody titer of 217 IU/ml anti-HBsAg and a regime of multiple daily injections (four aliquots of 2.5 ml) was applied via the subcutaneous route for seven days following the liver transplantation. Maintenance subcutaneous dosing of 2170 IU was administered every three weeks achieving serum anti-HBs titers from 500 to 1000 IU/L over five months post transplant.
The following reports show pharmacokinetic parameters of subcutaneous HBIG vis a vis intramuscular administration.
Thürmann et al. (“Pharmacokinetics and safety of a novel anti-HBs-enriched immunoglobulin in healthy volunteers after subcutaneous and intramuscular administration”. Eur J Clin Pharmacol. 2006; 62:511-512) investigated the pharmacokinetics of an anti-HBsAg-enriched immunoglobulin preparation which contains 635 IU anti-HBsAg/ml. The immunoglobulin was administered in an equal single dose of 30 IU/kg body weight either subcutaneously or intramuscularly. According to the paper comparable serum concentrations were obtained using both subcutaneous and intramuscular administration routes. Additionally, the bioavailability of the investigated HBIG preparation following subcutaneous and intramuscular administration was comparable to that following intravenous administration.
In a recent study Hooman et al. (“Antibody to hepatitis B surface antigen trough levels and half-lives do not differ after intravenous and intramuscular hepatitis B immunoglobulin administration after liver transplantation”. Liver Transpl. 2008; 14:435-442) compared pharmacokinetic parameters after IM and IV administration of 2000 IU HBIG. According to the report, although the area under the curve (AUC) levels were not measured during the first two weeks after HBIG administration, it was presumed that they were lower in IM as compared to IV administration. It is also indicated that the principles of pharmacokinetic parameters after SC administration are expected to be similar to IM administration. The report is silent on the levels of anti-HBs present in the circulation during the first two weeks following the different administration routes.
Recently (September 2009), the European Committee for Medical Products for Human Use (CHMP) recommended the granting of a marketing authorization for Zutectra®, a human hepatitis B immunoglobulin solution for subcutaneous administration. Zutectra® is manufactured from plasma of donors with high anti-HBs antibody titers (Biotest Pharma GmbH) and is intended for the prevention of hepatitis B virus re-infection after liver transplantation. It is available in 1 ml pre-filled syringe containing 500 IU anti-HBs antibodies. It is reported that effective anti-HBs-serum levels are achieved with weekly Zutectra® application.